Evidence That the Heme Regulatory Motifs in Heme Oxygenase-2 Serve as a Thiol/Disulfide Redox Switch Regulating Heme Binding

Li, Yang; Ragsdale, Stephen W.

doi:10.1074/jbc.m700664200

Cited by 73 publications

(155 citation statements)

References 46 publications

(70 reference statements)

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“…Out of the 264 residues in the truncated apoprotein, 212 residues were observed in molecule A, and 217 residues were observed in molecule B. Molecule A of apoHO-2 was lacking electron density in both the N-terminal (Met 1 -Met 28 ) and the C-terminal (Ser 242 -Lys 264 ) regions. The B molecule of apoHO-2 was lacking several N terminus (Met 1 -Met 30 ) and C terminus (Leu 249 -Lys 264 ) residues.…”

Section: Ho-2mentioning

confidence: 99%

“…HO-2 purification was performed as previously described with slight modification (28). The newly generated construct was transformed into E. coli strain BL21(DE3) for protein overexpression.…”

Section: Cloning Overexpression and Purification Of Human Ho-2-mentioning

confidence: 99%

“…Cleavage of the 52 amino acids at the C terminus of HO-1 affects nuclear import, leading to the activation of genes associated with protection against oxidative stress (27). In HO-2, the C-terminal region between residues 255 and 287 contains two heme regulatory motifs (HRMs), which form a thiol/disulfide redox switch that regulates heme binding affinity (28).…”

mentioning

confidence: 99%

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Comparison of Apo- and Heme-bound Crystal Structures of a Truncated Human Heme Oxygenase-2

Bianchetti

Ragsdale

et al. 2007

Journal of Biological Chemistry

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Heme oxygenase (HO) catalyzes the first step in the heme degradation pathway. The crystal structures of apo-and heme-bound truncated human HO-2 reveal a primarily ␣-helical architecture similar to that of human HO-1 and other known HOs. Proper orientation of heme in HO-2 is required for the regioselective oxidation of the ␣-mesocarbon. This is accomplished by interactions within the heme binding pocket, which is made up of two helices. The iron coordinating residue, His 45 , resides on the proximal helix. The distal helix contains highly conserved glycine residues that allow the helix to flex and interact with the bound heme. Tyr 154 , Lys 199 , and Arg 203 orient the heme through direct interactions with the heme propionates. The rearrangements of side chains in heme-bound HO-2 compared with apoHO-2 further elucidate HO-2 heme interactions. Heme oxygenase (HO)2 catalyzes the degradation of heme to free iron, carbon monoxide, and biliverdin in the presence of NADPH-dependent cytochrome P450 reductase. Seven electrons are transferred, and three molecules of oxygen are consumed in the degradation of one molecule of heme to biliverdin (Fig. 1). Subsequently, biliverdin reductase reduces biliverdin to bilirubin (1). Present in both bacteria and eukaryotes, HO is the only known enzyme that can degrade heme. HO not only plays a critical role in heme and iron homeostasis, but the products of heme degradation have important physiological functions (1, 2). Iron is the essential catalytic center for heme and many nonheme metalloenzymes and has crucial effects on cytoprotection (3, 4). Although CO is toxic at levels above ϳ500 ppm, it also is a signaling molecule (5, 6). CO has anti-apoptotic, antiinflammation, and anti-proliferation properties (7-9). Bilirubin is an antioxidant that is involved in resistance to oxidative stress (10, 11).Two HO isoforms have been reported in mammalian cells, heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2) (12). The mammalian HO-1 and HO-2 exhibit similar catalytic activities and share 55% identity and 76% similarity in humans (13,14). Another isoform, HO-3, was recently reported in rat; however, no activity was detected for this isoform, and it is considered a pseudogene (15). Plants contain several HOs, including one named HO-2, but these lack the C-terminal membranespanning region seen in mammalian HOs and are more closely related to the bacterial and insect HO-1 than to the mammalian HO-2 (13, 16).Although they are both membrane-bound proteins and their catalytic activities are similar, HO-1 and HO-2 are expressed in discrete tissues and exhibit very different patterns of expression (17). Although human HO-1 is an inducible protein whose expression is up-regulated by heat shock and oxidative stress conditions, HO-2 is constitutively expressed (17-22). HO-1 has been found in most tissues, with particularly high expression levels in liver and spleen; however, HO-2 is mainly found in the brain, testes, and carotid body (23-26).HO-1 and HO-2 exhibit two regions of sequence divergence: o...

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Section: Ho-2mentioning

confidence: 99%

Section: Cloning Overexpression and Purification Of Human Ho-2-mentioning

confidence: 99%

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Comparison of Apo- and Heme-bound Crystal Structures of a Truncated Human Heme Oxygenase-2

Bianchetti

Ragsdale

et al. 2007

Journal of Biological Chemistry

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“…Early studies indicated that these HRMs may bind heme directly [62,63]. However, recent reports have indicated that the HRMs affect catalytic efficiency without affecting heme affinity and do not result in additional hemebinding sites [64,65]. Rather, HRM1 and HRM2 form a thiol/ redox switch that modulates HO-2 affinity, on the basis of the redox environment.…”

Section: Structural Conservation Of Heme Oxygenase Isozymesmentioning

confidence: 99%

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

Rahman

Vukomanovic

Vlahakis

et al. 2013

J. R. Soc. Interface.

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The development of heme oxygenase (HO) inhibitors, especially those that are isozyme-selective, promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It is already known that HO has cytoprotective properties and may play a role in several disease states, making it an enticing therapeutic target. Traditionally, the metalloporphyrins have been used as competitive HO inhibitors owing to their structural similarity with the substrate, heme. However, given heme's important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), non-selectivity is an unfortunate side-effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort to develop novel compounds as potent, selective inhibitors of HO. This resulted in the creation of non-competitive inhibitors with selectivity for HO, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the structures of several complexes of HO-1 with novel inhibitors have been elucidated, which provided insightful information regarding the salient features required for inhibitor binding. This included the structural basis for non-competitive inhibition, flexibility and adaptability of the inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited in future drug-design strategies.

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“…A CP motívumok hem szabályozó motívumok (HRM-ek) központi szekvenciái, amelyek tiol/diszulfid redox kapcsolóként működve szabályozzák a hem kötődését a HO-2 enzimhez oxidatív stresszre és reduktív körülményekre adott válaszreakció során. Amikor a sejtek ki vannak téve az oxidatív hatásoknak, akkor a HRM-ek C-terminálisán lévő ciszteinek diszulfid állapotban vannak, amely kedvez a hem kötésnek, azonban redukáló körülmények között, az alacsonyabb affinitású ditiol állapot van túlsúlyban [229].…”

Section: Hemoxigenázok (Ho)unclassified

Az oxidatív stressz és az antioxidáns védelmi rendszer vizsgálata nehézfém kezelést követően pontyban és streptozotocin-indukálta diabéteszes patkány modellben

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Evidence That the Heme Regulatory Motifs in Heme Oxygenase-2 Serve as a Thiol/Disulfide Redox Switch Regulating Heme Binding

Cited by 73 publications

References 46 publications

Comparison of Apo- and Heme-bound Crystal Structures of a Truncated Human Heme Oxygenase-2

Comparison of Apo- and Heme-bound Crystal Structures of a Truncated Human Heme Oxygenase-2

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

Az oxidatív stressz és az antioxidáns védelmi rendszer vizsgálata nehézfém kezelést követően pontyban és streptozotocin-indukálta diabéteszes patkány modellben

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